Source: Available in capsules, tablets, chewable
tablets, syrups, elixirs, topical, and injectable forms in a variety
of prescription and over-the-counter medications. Products contain diphenhydramine
alone or in combination with other drugs such as pseudoephedrine and
acetaminophen. Diphenhydramine is also an ingredient in several Tylenol® (i.e.,
acetaminophen) preparations. Dimenhydrinate (Dramamine®) is a combination
of diphenhydramine and 8-chlorotheophylline in equal molecular proportions.

Medical and Recreational Uses: Used as an
antihistamine for the temporary relief of seasonal and perennial allergy
symptoms. Diphenhydramine is also used as a sleep aid and a cough suppressant,
and has been used as a centrally acting antitussive although the mechanism
for this action is unclear. Dramamine is used as a prophylaxis against
and for the treatment of motion sickness.

Potency, Purity and Dose: As an antihistamine,
recommended doses for adults is 25-50 mg diphenhydramine every 6-8 hours,
not to exceed 50-100 mg every 4-6 hours. For children, 12.5-25 mg three
or four times daily is recommended. As a sleep aid the dose is 50 mg
at bedtime. Adults can be given 10-50 mg intravenously or intramuscularly,
up to a maximum daily dose of 400 mg.

Route of Administration: Oral, injected, and
topical applications.

Pharmacodynamics: Diphenhydramine is a first
generation antihistamine and is a H 1 receptor antagonist. Antagonism
is achieved through blocking the effect of histamine more than blocking
its production or release. Diphenhydramine inhibits most responses of
smooth muscle to histamine and the vasoconstrictor effects of histamine.
The antagonism may also produce anticholinergic effects, antiemetic effects,
and significant sedative side effects.

Pharmacokinetics: Following oral administration
diphenhydramine is well absorbed from the gastrointestinal tract, is
widely distributed throughout the body, and is able to pass though the
blood-brain barrier. The oral availability is 61%, and 78% is bound in
plasma. Peak plasma concentrations are reached in 2-3 hours. Diphenhydramine
is metabolized to nordiphenhydramine (active metabolite), dinordiphenhydramine,
and diphenylmethoxyacetic acid. The plasma half-life is 8.5±3.2
hours; shorter and longer half-lives have been reported for children
and elderly subjects, respectively. Urinary excretion of unchanged diphenhydramine
is 1.9%.

Interpretation of Blood Concentrations: Following
a single oral dose of 50 mg, average peak plasma concentrations of 83
ng/mL diphenhydramine were detected at 3 hours, declining to 9 ng/mL
by 24 hours. A single oral 100 mg dose resulted in average peak plasma
concentrations of 112 ng/mL at 2 hours post dose. Effective antihistamine
concentrations are greater than 25 ng/mL, drowsiness can be observed
at 30-40 ng/mL, and mental impairment may be observed with concentrations
above 60 ng/mL.

Interpretation of Urine Test Results: Less
than 2% of an oral dose is excreted in the 24 hour urine as unchanged
parent drug, while approximately 11% is eliminated as its glucuronide
conjugate.

Effects: First generation H 1 antagonists
can both stimulate and depress the CNS. Stimulation results in restlessness,
nervousness and inability to sleep, while depressive effects include
diminished alertness, slowed reaction time and somnolence. Diphenhydramine
is particularly prone to cause marked sedation. Drowsiness, reduced wakefulness,
altered mood, impaired cognitive and psychomotor performance may also
be observed.

Side Effect Profile: Includes agitation, anticholinergic
side effects such as dry mouth, confusion, dizziness, drowsiness, fatigue,
disturbed coordination, irritability, paresthesia, blurred vision, and
depression. In overdose, symptoms may include excitement, ataxia, tremor,
sinus tachycardia, fever, hallucination, athetosis, convulsions or seizures,
hypotension, deep coma, cardiorespiratory collapse, and death. Fixed
and dilated pupils are also observed. Gastrointestinal symptoms are less
with diphenhydramine than with other H 1 antagonists.

Duration of Effects: Dose-dependent, however,
following oral administration of therapeutic doses, peak plasma concentrations
are reached in 2-3 hours and effects usually last 4-6 hours.

Tolerance, Dependence and Withdrawal Effects: Some
tolerance may develop to the sedative effects of diphenhydramine with
repeated oral dosing. No reported dependence or withdrawal effects with
doses recommended.

Drug Interactions: Effects of diphenhydramine
are increased by the presence of alcohol, MAOI’s, diazepam, hypnotics,
sedatives, tranquilizers, and other CNS depressants. Alcohol enhances
such effects as drowsiness, sedation and decreased motor skills. These
decrements in effect are more pronounced in the elderly.

MAOI’s prolong and intensify the anticholinergic effects of diphenhydramine.

Performance Effects: All first generation
antihistamines, including diphenhydramine, have been demonstrated to
diminish cognitive and psychomotor performance in healthy volunteers.
Impairment might even be of greater clinical significance in patients
when the allergic disorder per se adversely affects CNS function, as
suggested in studies in which a reduction in cognitive functioning in
patients was exacerbated by diphenhydramine . Laboratory studies have
shown diphenhydramine to decrease alertness, decrease reaction time,
induce somnolence, impair concentration, impair time estimation, impair
tracking, decrease learning ability, and impair attention and memory
within the first 2-3 hours post dose. Significant adverse effects on
vigilance, divided attention, working memory, and psychomotor performance
have been demonstrated. It is important to note that impairment has been
shown to occur even in the absence of self-reported sleepiness or sedation.
Concurrent use of diazepam and diphenhydramine caused significant performance
decrements at 2 hours, and to some degree up to 4 hours.

Effects on Driving: The drug manufacturer
states that p atients should be warned about engaging in activities requiring
mental alertness such as driving a car. Diphenhydramine has repeatedly
been shown to severely impair tracking and reaction time performance
in actual on-the-road driving tests. Single doses of 50 mg have been
shown to cause significant impairment during a 90 km highway test (measuring
vehicle following, constant speed and lateral position). In contrast,
single 25-100 mg doses caused no significant driving effects during a
short 15 minute driving test. Using the Iowa Driving Simulator, Weiler
et al, 2000 compared the effects of a single oral dose of 50 mg diphenhydramine
to the effects corresponding to a blood alcohol concentration of 0.1
g/100 mL. Diphenhydramine caused significantly less coherence (ability
to maintain a constant distance) and impaired lane keeping (steering
instability and crossing center line) compared to alcohol. Overall driving
performance was the poorest after taking diphenhydramine, and participants
were most drowsy after taking diphenhydramine (before and after testing).
The authors concluded that diphenhydramine clearly impairs driving performance,
and may have an even greater impact than does alcohol on the complex
task of operating a motor vehicle.

Panel’s Assessment of Driving Risks: Single
therapeutic doses of diphenhydramine have been shown to significantly
impair psychomotor performance during the first 4 hours, and may have
a greater impact on driving performance than alcohol.

Ramaekers JG, O'Hanlon JF. Acrivastine, terfenadine and diphenhydramine
effects on several aspects of actual driving performance as a function
of dose and time after dosing. Eur J Clin Pharmacol 1994;42:363-9.